The lysosome is a cytoplasmic organelle that functions to degrade macromolecules such as proteins, polynucleotides, polysaccharides, and lipids. The lysosome encloses an acidic environment and contains hydrolase enzymes which catalyze the hydrolysis of biological macromolecules. The lysosome has also been found to play a role in the uptake of molecules via endocytosis.
Lysosomal storage diseases occur when a lysosomal protein is deficient or mutant. In many cases, this protein is an enzyme, and abnormal deposits of the substrate of the deficient enzyme accumulate in the cell. In other cases, the deficient protein is involved in trafficking, post-translational processing, or protection or activation of a lysosomal enzyme. In still other cases, the defective protein is not an enzyme but exists in the intra-lysosomal space or spans the lysosomal membrane. The function of some of these proteins is presently unknown. There is extensive clinical and biochemical heterogeneity within the lysosomal storage diseases, which include most of the lipid storage disorders, the mucopolysaccharidoses, the mucolipidoses, and glycoprotein storage diseases. Currently there are approximately 50 lysosomal storage disorders known including Niemann-Pick disease, Fabry's disease, Gaucher disease, etc. The disorders are typically progressive and frequently are fatal in childhood or adolescence. Genetic counseling is important in the management of these diseases, and specific therapies such as enzyme replacement therapy are promising but expensive. Typically the care for these patients is largely symptomatic.
Lysosomal storage disorders (LSDs) are a group of approximately 50 inherited metabolic diseases that result from cellular deficiencies of a specific lysosomal enzyme, receptor target, activator protein, membrane protein, or transporter that leads to pathogenic accumulation of substances in lysosomes, causing buildup of the substrate, resulting in deterioration of cellular and tissue function. The hallmark feature of LSDs is the abnormal accumulation of metabolites in the lysosomes which leads to the formation of large numbers of distended lysosomes in the perikaryon. A major challenge to treating LSDs (as opposed to treating an organ specific enzymopathy, e.g., a liver-specific enzymopathy) is the need to reverse lysosomal storage pathology in multiple separate tissues. Lysosomal storage disorders occur in approximately 1 in 5,000 to 1 in 10,000 live births and display considerable clinical and biochemical heterogeneity. The majority of lysosomal storage disorders are inherited as autosomal recessive conditions although two examples of X-linked are Hunter syndrome (MPS II) and Fabry disease. The extent and severity of the lysosomal storage disorder depend on the type and amount of substrate that accumulates, but almost all disorders are progressive. Most disorders have both central nervous system and systemic manifestations, whereas some affect either just the central nervous system or tissues outside the nervous system. Many patients with lysosomal storage disorders die in infancy or childhood, and patients who survive to adulthood often have a decreased lifespan and significant morbidity. Examples of lysosomal disorderes include defective metabolism of mucopolysaccharides (MPS) I-IX (Hurler, Scheie, Hunter, Sanfilippo, Morquio, glycosaminoglycans Maroteaux-Lamy, Sly diseases, hyaluronidase deficiency), defective degradation of glycan aspartylglucosaminuria, fucosidosis, mannosidosis, glucosphingolipids Schindler disease, sialidosis type I, defective degradation of glycogen (Pompe disease), defective degradation of globotriaosylceramide (Fabry disease), defective degradation of lipids (Farber disease), Gaucher disease (types sphingolipid components 1-3) GM1-gangliosidosis, GM2-gangliosidoses (Tay-Sachs disease, Sandhoff disease, GM2 activator disease), Krabbe disease, metachromatic leukodystrophy, Niemann-Pick disease (type A or B), pycnodysostosis, defective degradation or transport of lipofuscins causing ceroid lipofuscinosis (multiple types with different of cholesterol, cholesterol esters, or defects, some not known yet), cholesterol ester storage disorders and other complex lipid storage diseases, Niemann-Pick disease type C, Wolman disease, deficiencies of multiple lysosomal sulfatases, galactosialidosis, mucolipidosis types I, III and IV, cystinosis, sialic acid storage disorder, Marinesco-Sjogren syndrome, Hermansky-Pudlak syndrome (several forms), Chediak-Higashi syndrome, and Danon disease.
Gaucher disease is the most prevalent lysosomal storage disorder and results from the deficiency of glucocerebrosidase (GC; EC 3.2.1.45) in all tissues. This enzyme deficiency results in accumulation of glucosylceramide in lipid-laden macrophages (called Gaucher cells) in the reticulendothelial system including liver, spleen, lung, and bone marrow. Gaucher disease has been categorized into three major phenotypes: type 1, non-neuropathic; type 2, acute infantile neuropathic; and type 3, chronic neuropathic. The spectrum of illness severity for type 1 Gaucher disease is broad. Children and adults can be asymptomatic or may have severely debilitating symptoms, including skeletal degeneration, anemia, thrombocytopenia and hepatosplenomegaly. Symptoms can present at any age. Although type 1 Gaucher disease is more common among the Ashkenazi Jewish population, it occurs in all ethnic groups. Type 2 Gaucher disease is rapidly progressive. By six months of age, most type 2 infants have brainstem dysfunction and succumb to complications such as respiratory arrest or aspiration pneumonia at 18-24 months of age. Type 3 Gaucher disease patients develop neurological abnormalities at a later age than type 2 patients; most only develop a subtle horizontal saccadic eye movement defect.
Gaucher disease is the most common lysosomal storage disorder, affecting approximately 8,000 to 10,000 people worldwide. In Gaucher disease, the activity of a lysosomal enzyme, known as acid-beta-glucosidase or glucocerebrosidase (GlcCerase), is significantly decreased owing to one of approximately 200 mutations in the GBA gene that codes for the enzyme. This condition is inherited in an autosomal recessive pattern, which means that people with mutations in both copies of the GBA gene develop Gaucher disease. Reduced GlcCerase activity leads to the accumulation of glucocerebroside (also called glucosylceramide) in tissues, including the spleen, liver, lungs, bone marrow, and sometimes in the brain. This accumulation of glucocerebroside is believed to cause the various symptoms and signs of Gaucher disease, including an enlarged liver and spleen (splenomegaly), skeletal disorders, and, in some instances, lung, kidney, and central nervous system impairment. There is also an association between Gaucher disease and Parkinson disease or Parkinson-like disorders that affect movement and balance (parkinsonism). Parkinsonism has been observed in patients with Gaucher disease and in disease gene carriers (Lesage et al., 2011). The signs and symptoms of parkinsonism in such persons may include: intention tremors, rigidity and bradykinesis, expressionless facies, slurred or monotonous speech, myoclonic jerks, olfactory loss, and avascular osteonecrosis (Neudorfer et al., 1996; Bultron et al., 2010). Lewy body dementia has also been reported in some subjects. Effective dietary and/or pharmaceutical interventions for one or more of these signs and symptoms would significantly improve the quality of life in such persons.
Currently, enzyme-replacement therapy (ERT) and substrate-reduction therapy are the only approved treatment options for patients with Gaucher disease (for a review see Harmanci, 2008). ERT, using recombinant imiglucerase, improves the visceral and hematologic manifestations of the disease, but it is not effective in neuropathic forms of Gaucher disease. Also, the cost of ERT is approximately $200,000 per year per patient, which is prohibitive for many patients, and there is insufficient supply of recombinant enzyme to meet the medical needs in the market place. Furthermore, recombinant imiglucerase must be administered intravenously, which is a disadvantage. The first oral therapeutic agent for Gaucher disease is miglustat (N-butyldeoxynojirimycin), an iminosugar inhibitor of glucosylceramide synthase, which is used for substrate-reduction therapy. Miglustat produces clinical improvement in selected patients with mild or moderate disease, but the responses are slower and less robust than those observed with ERT. Other potential therapies for Gaucher disease are still in development (Futerman, 2004).
There is a long felt need for methods to prevent and/or treat lysosomal storage disorders that provide patients with a higher quality of life and achieve a better clinical outcome. In particular, there is a need for methods to prevent and/or treat Gaucher's disease that provide patients with a higher quality of life and achieve a better clinical outcome.
Thus, there has gone unmet a long felt need for improved methods and compositions, for the treatment of Gaucher disease. In particular there has gone unmet a long felt need for methods and compositions, that are orally available and cost-effective. There remains a need for additional therapies to treat these often fatal diseases. The present systems, compositions and methods provide these unmet long felt needs as well as other advantages not provided by prior therapies.